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BRITISH MEDICAL JOURNAL

19 JUNE 1976

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might govern the response of the central nervous system to a common product of different viruses. Possibly the cardiotropism of viruses, such as those of Coxsackie group B, which is currently unexplained, has an analogous basis. This in turn could account for the association we have described between valvular disease and the HLA antigens A29 and AW30,131-that is, these HLA antigens might act as a conditioning factor8 which occasionally transforms a mild viral myocarditis-a common occurrence9into a severe pancarditis. Our study does not directly implicate viruses as a cause of acquired valvular heart disease. It does, however, provide further evidence which is inconsistent with the traditional "rheumatic" explanation. It also indicates a possible line of research into the aetiology of obscure heart disease which has not yet been explored.
We thank the physicians and surgeons of the cardiothoracic unit, Northern General Hospital, Sheffield, for allowing us access to patients under their care, and Dr I R Dunsmore, department of probability and statistics, University of Sheffield, who kindly undertook the statistical analysis of the results. CW was in receipt of British Heart Foundation Research Grant No 496, and KG and RWD were in receipt of a medical research grant from the Trent Regional Health Authority.

valvular heart disease but no rheumatic history. Generally, the main distinguishing characteristics of this subgroup are a more equal sex distribution, isolated mitral valve disease, a relatively short history of symptoms before surgery, and, in many cases, the need for surgery at a comparatively early age. These findings are difficult to equate with the generally accepted concept of the aetiology of acquired valvular heart disease. This traditional view is that virtually all cases are rheumatic. In patients with no history of rheumatic fever or chorea their valvular disease is usually attributed to subclinical rheumatic carditis. Since it is not possible to investigate patients at the time of onset of subclinical carditis, however, the assertion that all such cases are rheumatic is speculative. It could, nevertheless, be argued for the traditional view that patients with no rheumatic history-that is, those with allegedly subclinical rheumatic carditis-differ fundamentally from those who have had classical rheumatic fever and that this may, in some way, account for clinically observed differences between those with and those without a rheumatic history. In this context the AW19 antigens might be a factor predisposing to the development of subclinical, as opposed to overt, rheumatic carditis. This line of reasoning, however, does not explain why patients with AW19 antigens differ clinically from those other patients with no rheumatic history (group 2) who are also assumed to have had subclinical rheumatic carditis. The aetiology of these cases of valvular heart disease, if not rheumatic, is unknown. It has, however, been suggested that viruses may sometimes be implicated. In animals viruses can produce valve lesions with many of the characteristics of chronic rheumatic heart disease in man.' There is also evidence in man 4 that viruses' and similar organisms6 may cause valvular damage. Other suggestions have been made which postulate a link between HLA antigens and some virus infections. For example, the neurotropism of polio virus appears to be partly dependent on the presence of HLA antigens A3 or B7.7 In more general terms it has been suggested that these particular antigens

References

1Ward, C, et al, 2

Tissue Antigens, in press. Gelsthorpe, K, and Doughty, R W, Medical Laboratory Technology, 1971, 28, 22. 3Sun, S C, et al, British Journal of Experimental Pathology, 1967, 48, 655. 4 Sainani, G S, Krompotic, E, and Slodki, S J, Medicine, 1968, 47, 133. 5 Burch, G E, and Colcolough, H L, Annals of Internal Medicine, 1969, 71,
963. 6 Ward, C, and Ward, A M, Lancet, 1974, 2, 734. 7Morris, P J, and Pietsch, M J, Lancet, 1973, 2, 848. 8 Pearce, J M, Archives of Pathology, 1939, 28, 827. 9Verel, D, et al, British Heart Journal, 1974, 36, 395.

Cows' milk protein intolerance: a possible association with gastroenteritis, lactose intolerance, and IgA deficiency
MARY HARRISON, ANNE KILBY, J A WALKER-SMITH, N E FRANCE, C B S WOOD
British Medical Journal, 1976, 1, 1501-1504

Summary Twenty-five children with cows' milk protein intolerance were studied. Twenty had presented with an illness clinically indistinguishable from infantile gastroenteritis; an enteropathogenic Escherichia coli was isolated from the stools in two children, and in six another member of the family simultaneously developed acute diarrhoea and vomiting. Twenty-three children had lactose intolerance

secondary to cows' milk protein intolerance. Eight out of 20 children were found to be partially IgA deficient. An acute attack of gastroenteritis, in damaging the small mucosa, may act as a triggering mechanism in cows' milk protein intolerance, and a deficiency in IgA may be a predisposing factor in so far as it allows the patient to become sensitised to foreign protein.

Queen Elizabeth Hospital for Children, Hackney Road, London E2 8PS


MARY HARRISON, MRCP, DCH, clinical lecturer in child health ANNE KILBY, MB, MRCP, research fellow in paediatric gastroenterology J A WALKER-SMITH, MRCP, FRACP, consultant senior lecturer N E FRANCE, MB, FRCPATH, consultant pathologist C B S WOOD, DCH, FRCP, professor of child health

Introduction Cows' milk protein intolerance is the clinical syndrome due to sensitisation to cows' milk protein antigens. The resulting immunological reaction causes symptoms that may be predominantly gastrointestinal, respiratory, or dermatological.' Our purpose here is to report the possible role of gastroenteritis in the aetiology of cows' milk protein intolerance, describe the clinical and laboratory features of a group of children diagnosed as having the condition, and offer a hypothesis about the possible relationship between cows' milk protein intolerance, gastroenteritis, and lactose intolerance.

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Patients and methods
We studied 25 children with cows' milk protein intolerance who were admitted to the academic unit at the Queen Elizabeth Hospital for Children, London, in the three years from October 1972. The diagnosis of cows' milk protein intolerance was based on: (a) the presence of symptoms on a diet containing cows' milk, (b) the disappearance of symptoms on withdrawal of cows' milk, and (c) one or more positive reactions to milk challenges, with return of symptoms and the appearance of various associated phenomena (see tables II-VII). Twenty-three of the children had been fed on a cows' milk preparation from birth, while two had been breast-fed initially but received cows' milk after an acute episode of diarrhoea and vomiting. Lactose tolerance test-An oral load of 2 g lactose/kg body weight was given before a milk challenge to 22 children. All stools passed for 24 hours afterwards were observed and tested for reducing substances. Most patients were continued on feeds of 7qo lactose for 24 hours after the oral load. Milk challenge-Challenges were performed after periods of milk withdrawal varying from one week to 12 months (mean 3 5 months)that is, six weeks to 13 months after the initial episode of gastroenteritis (mean 6-5 months). Blood samples were taken before and 24 hours after the challenge for eosinophil counts. 5 ml of fresh pasteurised cows' milk or a dried milk preparation were given, followed by a further 10 ml one hour later if there had been no reaction. No further cows' milk was given for 24 hours. Cows' milk was then reintroduced, starting at a dilution of 1/5 and increasing by 1/5 a day. All stools were tested for reducing substances using Clinitest tablets and for occult blood using Occultest tablets. Temperature was recorded every four hours and weight every 12. Small intestinal biopsy-This was performed on one or more occasions in 18 children using a paediatric modification of the Crosby Capsule. The specimen was taken from close to the duodenojejunal junction. It was examined and photographed under the dissecting microscope, and subsequently by light microscopy, the pathologist being unaware of the clinical details. The findings were graded as follows: N = normal; i = minimal or doubtful lesion; + = short wide villi, usually with some normal surface epithelium, increased cells in lamina propria, and rather longer crypts (parital villous atrophy); + + =thickened ridges, usually with normal surface epithelium, moderate increase of cells in lamina propria, elongated crypts (moderate villous atrophy); and + ++ = flat surface covered by abnormal epithelium with excess cells in lamina propria and elongated crypts (subtotal villous atrophy). Immunofluorescent staining was performed on 13 biopsy specimens from five children. Mucosal disaccharidase activities were measured by the method of Burgess et al.2 Duodenal juice was examined for Giardia lamblia. If the initial biopsy was abnormal it was repeated with disaccharidase assay before the milk challenge. Other investigations-These included serial estimations of serum immunoglobulins by single radial immunodiffusion technique, estimation of milk precipitins by gel diffusion, and prick tests using whole cows' milk, cx-lactalbumin, and cows' milk casein antigens (Bencard). A family history of atopy or cows' milk protein intolerance in a first-degree relative was sought.

BRITISH MEDICAL JOURNAL

19 JUNE 1976

Three children who had been fed on cows' milk from birth presented with gastroenteritis at 9, 10, and 15 months. Within a month they developed cows' milk protein intolerance and two developed urticaria on drinkin"g milk. Five children presented with chronic diarrhoea or vomiting, or both, of three to seven months' duration with failure to thrive, the weight being below the 3rd percentile in three and between the 3rd and the 10th percentile in two. In one of these a diagnosis of coeliac disease was possible. Immunological results-Serum IgA levels were below the lower limit of normal for age on first testing in eight of the 20 tested. In only one child was the serum IgA level raised at any time (tables II and III). Association with lactose intolerance-After rehydration with intravenous fluids or an oral glucose and electrolyte mixture all 20 children who presented with acute gastroenteritis failed to tolerate cows' milk feeds; diarrhoea, vomiting, and failure to gain weight recurred. Sixteen of these children developed 0 5-20" reducing substances in the stools, and paper chromatography of the stools confirmed lactose malabsorption in the 13 tested (table IV). Disaccharidase activities were depressed in three out of seven of these children. After an interval of lactose and milk withdrawal varying from two to nine months (mean 3-8 months) lactose tolerance tests were performed. All 20 children showed a rise in blood glucose above the fasting level of greater than 1-12 mmol/l (20 mg/100 ml). Seven per cent lactose feeds were tolerated, and no child developed diarrhoea. Disaccharidase activities were normal in all but one child (case 12) (table V). Thus there was no clinical evidence of lactose intolerance before milk
TABLE iI-Immunological results
Prick tests
Milk

Casein
16 9

Lactal-

bumnin
16 10

Cows' milk precipitins


23 12

Serum IgA below normal


20 8

No tested No positive

..

16 13

TABLE IiI-Details of children with low serum IgA levels


Case No
5 6
7

Age (months) 3 9 25
7

Serum

IgA (IU/ml)
3.5 8-5 15
10-6
21

Mean

IgA for age (IU/ml)


I1 21 49

2 SD (IU/ml) 4-28
11-49 21-92

Range for age

20 28
3 17

52-8
0 31 0 17-6

21 49 60
11

11-49 21-92

25-99
4-28 21-92

49
60 60 28 11 49
11 18 49

14
17 22

26 35
2 11 2 17
2

25-99 25-99 4-28 18-53 4-28 21-92 4-28 7-42 21-92 11-49 18-53

5 14
4-2 0

11

Results
There were 18 boys and seven girls in the study. A positive family history of atopy was obtained in all the 19 families in whom it was asked for. Three of the fathers had required a special diet in infancy for cows' milk protein intolerance. The age of onset of symptoms is shown in table I; 19 children were aged 6 weeks or under. Twenty children presented with the classical features of infantile gastroenteritis-that is, with an acute illness characterised by the sudden onset of profuse diarrhoea and vomiting. An enteropathogenic Escherichia coli was isolated from the stool at the time of the acute episode in two children and five weeks later in another. No other stool pathogens were isolated at any time. There was circumstantial evidence of infective diarrhoea in six children, another member of the family having developed diarrhoea and vomiting at the same time.

23

4
17
25 6

0 13
28 7

15

21 28

TABLE iv-Features of sugar malabsorption in 20 children presenting with gastroenteritis


No tested

positive
16 13 20 (1-18-4-59; mean 2-13) 0 0 0 20

No

TABLE I-Age at onset of symptoms


Age(weeks): No of children: 1 5 2 3 3 8

21

10 1

11

12 1

45 1

60 1

64 1

Stool reducing substances of 05-20, on initial change from clear fluids to cows' milk Presence of lactose and lactic acid on initial stool chromatography Lactose tolerance test; rise in blood glucose of >1-12 mmol/l. Stool reducing substances during lactose tolerance test. Stool reducing substances with 70,0 lactose feeds Stool reducing substances before milk challenge Stool reducing substances after milk challenge

17
13 20

20 15 20 20

with abnormal amounts of reducing substances occurred in all 20 children and in a further three of the total studied. Loss of disaccharidase activity was shown in five children who underwent biopsy after
TABLE

JUNE 1976 challenge. Nevertheless, within hours of a milk challenge diarrhoea


19

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challenge. Thus in 720,, there was evidence of sugar malabsorption after a rositive milk challenge. Small intestinal biopsy-Of the nine children who underwent biopsy before milk withdrawal none had a normal small intestinal mucosa (table VI). Two had subtotal villous atrophy (+ + +) (cases 19 and 24) and one (case 5) had a patchy lesion of moderate to subtotal villous atrophy (+ ++/+++ -). These three children may have had coeliac + disease. One patient (case 5) presented with sudden onset of diarrhoea and vomiting at three weeks of age, having had only one teaspoonful of cereal. Another (case 19) was well until he had E coli gastroenteritis at nine months of age, gluten having been introduced at six weeks; after the infection he could not tolerate milk. Another child (case 24) presented with chronic diarrhoea and vomiting, which preceded the introduction of gluten by four weeks. A pronounced increase in mucosal damage was seen in all five children who underwent biopsy after a positive milk challenge (table VI). This was accompanied by a rise in the number of immunoglobulin-containing cells in the lamina

v-Lactase activities in small intestinal


Initial level (and normal range)

mucosa.

parentheses) varies according to site of small bowel biopsy


Case No
2 5 6* 7 9 11 12 13 14 15* 19 20 21 22 23 24*

Normal range (given in


Level after positive milk challenge (and normal range)

(umlmnin/g)

Level before positive milk challenge (and normal range) m (p.m/min g)

(mrmnrin/g)

08 22 16 30

(2 7-9 3) (2 0-16-2) (2-9-9 3) (0 2-3 5)

50
09

(27-93)
(2 7-9 3)

5 1 (2-0-16 2) 0-6 (2 7-9 3)

(2 0-16-2) (2 7-9 3) (02-35) (0 2-3 5) (0 2-3 5) (2 0-16 2) (0-2-3 5) (2-7-9 3) (2 0-16 2) (02-35) (2-7-9 3) (20-162) (2 0-16-2) (2-0-16-2) 2-3 2-3 2 1 (0 5)

45 26 29 05 05 66 11 30 29 64 24 50 37 21

(27-93)

2-6 (2-7-9 3)

0 1 (02-35) 6-2 (2 8-18 7)

propria.
Milk challenge-The features of positive milk challenges are shown in table VII. In most younger children the reaction was rapid with onset of symptoms within 24 hours. In four older children it occurred over two to three weeks. Age of recovery-The mean age of recovery was 18-4 months (range seven to 45 months). Four children were still intolerant to cows' milk protein, and 10 suffered from asthma and four from eczema at the time of writing.

0 1 (2-8-18-7) 0-8 (2-0-16-2)

*Presented with chronic diarrhoea and failure to thrive. Maltase and sucrase activities were measured, and in all cases reflected the lactase activities. Conversion: SI to traditiontal uinits-Lactose: 1 tmol/min/g Z 0 36 mg/min/g.
TABLE

Discussion
vI-Results of small initestinal biopsies
gastroenteritis)
Initial biopsy (months since
A4onths of milk b efore challenge

Case No
2
3
5

Biopsy

(months since challenge challenge


,astroenteritis) 4 75 (7 75)
20 (21-5)

before
-+

of milk

Result

after challenge
+ +

Biopsy

Positive

15 (16 75)

+ +
N N

PN NtD
ND ND

Positive

++ + + + (1 25)

~+1
6*
7

9 (10) + 2 M,GF (12) 4 M, GE (14) [0 M, (24)

4 GF (5 25) 7 GF (8)

GF

-e+

++

Positive
ND

+/+ +(75)
+ + + +

165 19 (195)
4 (4-5) 4 (6)

Positive
Negative
Positive

N
N

11
12 13
14

(2) (8)

5 (13) 2 (4) 10 (11) 2 (12)


5 (12 5) 3 GE (7) 2 31
0-5 (1)

N + N
N
+ +

Positive Negative Positive Positive Positive


Negative
Positive

++ + +/+ + + ++

15*
18
19
+ +

(35)

+ +.+ (4)

++ +++

20* 21 22
23
+ + (0 75)

8 (11)

N +,' ++

Positive
Positive

Negative

N/+
N

Positive Positive

13 (14 5)

4 (55)

Positive

0 5 (3)
+

3 (4 75)

Positive

Positive

24*

9 GF

Negative

*Patient did not have gastroente GF = On gluten-free diet. M = C:)n

milk-containing diet. ND = Not tested.

Gastroenteritis precipitating cows' milk protein intolerance has not been reported. Circulating levels of unaltered foreign protein are higher after feeding protein to infants recovering from infantile diarrhoea than after protein administration to normal infants. This is thought to be due to increased absorption from the damaged gastrointestinal tract.'3 In this study two children were shown to have had an enteropathogenic E coli infection, and there was strong clinical evidence of acute gastroenteritis preceding the development of cows' milk protein intolerance in a further 18 of the 25 children. Proof of the diagnosis of gastroenteritis must wait until the technique of virus identification in stools becomes readily available. On the basis of our findings, however, we suggest that an acute attack of gastroenteritis may act as a triggering mechanism in the pathogenesis of cows' milk protein intolerance, sensitisation to cows' milk protein occurring when the gastrointestinal tract is damaged by infection, resulting in the absorption of cows' milk protein antigens. Since the work of Burke et al in 1965,4 it has been widely accepted that milk intolerance after gastroenteritis in infancy is due to lactase deficiency secondary to the small intestinal damage produced by infection, yet some workers have shown that sugar malabsorption may occur in association with cows' milk protein intolerance5 6 and have even suggested that lactose intolerance occurs secondary to cows' milk protein intolerance.7 8 We saw infants who had clear evidence of lactose intolerance at diagnosis with an abnormal small intestinal mucosa and depressed lactase activity. This state of lactose intolerance disappeared after a period on a hypoallergenic lactose-free diet, with mucosal healing and rise of lactase levels to normal, only to recur after a milk challenge, with evidence of recurrence of mucosal damage and fall of lactase levels in those studied. An abnormal immunological reaction may have occurred within the small intestinal mucosa of these children in response to ingestion of cows' milk, causing damage to mucosal cells and depression of disaccharidase

TABLE

vII-Results of milk challenge


Vomiting
Weight loss >300 g in 24 h
Rise in temperature to - 38 C substances in stools of

Reducing

Rash
25

Urticaria
25

Wheezing
25

Anaphylaxis
25

~~0-5-2

25 22_

24

25I24
__

19!

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BRITISH MEDICAL JOURNAL

19 JUNE 1976

activities resulting in lactose intolerance secondary to cows' milk protein intolerance. The rise seen in the number of immunoglobulin-containing cells of the lamina propria after a positive milk challenge supports this suggestion, details of which will be given in another paper.9 Insufficient attention has been paid to this relation between lactose intolerance and cows' milk protein intolerance, resulting in underdiagnosis of the protein intolerance. This also explains why breast milk with its lactose content of 194 mmol/l (7 g/ 100 ml) may fail in treatment. A lactose-free preparation is recommended in the treatment of cows' milk protein intolerance. The association between coeliac disease and cows' milk protein intolerance is well known.10 11 Three children with possible coeliac disease were included in this study. They illustrate the difficulty of distinguishing between the two conditions and the need for serial small intestinal biopsies coupled with accurate dietary information. They probably had cows' milk protein intolerance, but it is essential that a final biopsy is performed two years after the reintroduction of gluten to exclude coeliac disease, as cows' milk protein intolerance may be a precursor of coeliac disease."1 Why did sensitisation to cows' milk occur in these few children, when most recover uneventfully from gastroenteritis ? A partial explanation may come from the observation that 40') of the 20 infants tested had a serum IgA level below the lower limit of normal for age at the time of diagnosis and that clinical recovery tended to coincide with a return of the IgA level to normal. Gerrard et al'2 postulated that sensitisation to foreign protein would be apt to occur in the newborn when the infant's rate of synthesis of serum and secretory IgA is low. Taylor et all reported that IgA deficiency at three months is associated with the development of atopy and cows' milk protein intolerance in the offspring of reaginic parents. A family history of atopy was a notable feature in this study, although a control group was not included, and probably IgA deficiency may be a predisposing factor in the development of cows' milk protein intolerance.

Acute gastroenteritis
Smoll intestinal

l~P

Excess absorption of foreiqn protein


ref 14
l

mucosal damage rf 3l

rrefs

4.7.8

Secondary
lactase deficiency

refs 4.7. 8

Sensitisation to cows' milk protein


Cows' milk protein intolerance

Secondary l actose intolerance

Hypothesis on possible association of gastroenteritis and lactose intolerance with cows' milk protein intolerance.

A hypothesis based on the findings in this study, concerning the possible association of gastroenteritis and lactose intolerance with cows' milk protein intolerance, is indicated in the figure.

References
Freier, S, and Kletter, B, Australian Paediatric Journal, 1972, 8, 140. Burgess, E A, et al, Archives of Disease in Childhood, 1964, 39, 431. 3Gruskay, F L, and Cooke, R E, Pediatrics, 1965, 16, 763. 4 Burke, V, Kerry, K R, and Anderson, C M, Australian Paediatric Journal, 1965, 1, 47. 5 Holzel, A, Paediatric Clinics of North America, 1965, 12, 651. 6 Kuitunen, P, et al, Archives of Disease in Childhood, 1975, 50, 350. Matsumura, R, Kuroume, T, and Amada, K, J7ournal of Asthma Research, 1971, 9, 13. 8 Harrison, M, Wood, C B S, and Walker-Smith, J A, Archives of Disease in Childhood, 1975, 50, 746. 9 Kilby, A, ct al, in preparation. 0 Visakorpi, J K, and Immonen, P, Acta Paediatrica Scandinavica. 1967. 56, 49. Fallstrom, S P, Winberg, J, and Anderson, H J, Acta Paediatrica Scandinavica, 1965, 54, 101. 12 Gerrard, J W, et al, Acta Paediatrica Scandinavica, 1973, suppl No 234. 13 Taylor, B, et al, Lancet, 1973, 2, 111. 14 Kuitunen, P, et al, Acta Paediatrica Scandinavica, 1973, 62, 585. 15 Barnes, G L, and Townley, R R W, Archives of Disease in Childhood, 1973, 43, 343.
2

Explanations for weight loss after ileojejunal bypass in gross obesity


T R E PILKINGTON, J-C GAZET, LISA ANG, R S KALUCY,
British Medical Journal, 1976, 1, 1504-1505

A H CRISP,

SALLY DAY

Introduction
Payne and De Wind' in 1969 pioneered ileojejunal bypass for the treatment of gross obesity, a condition which can only rarely be treated by other means. After this operation about 40 kg of weight is lost over two years and the resulting lower weight is then easily maintained. It has usually been assumed that the weight loss is due to the malabsorption of fat and protein. This explanation, however, has never been checked quantitatively. We report here the measurement of faecal calories before and after bypass.

Summary Twenty grossly obese patients underwent ileojejunal bypass operations. Measurements of calories lost in faeces showed that the malabsorption could not account for the weight loss. Furthermore, the malabsorption was not decreased two years after bypass, when weight was no longer being lost. Dietary restriction is therefore largely responsible for the weight loss and increased food intake for weight maintenance.
St George's Hospital, London SW17 OQT T R E PILKINGTON, MD, FRCP, professor of medicine R S KALUCY, FRACP, MRCPSYCH, senior lecturer in psychiatry J-C GAZET, MS, FRCS, consultant surgeon A H CRISP, MD, FRCPSYCH, professor of psychiatry LISA ANG, BSC, MSC, DIC, research assistant SALLY DAY, district dietitian

Patients and methods


Seventeen women with a mean weight (+ SD) of 117 71 14 77 kg and three men weighing 142-33 + 30 54 kg had a bypass operation in which 4 in (10-2 cm) of the proximal jejunum was anastomosed to 10 in (25 4 cm) of terminal ileum.' Before operation the patients were admitted for metabolic study. The women were given diets supplying 9 489 MJ (2270 kcal) and the men diets supplying 11-620 MJ (2780 kcal) on each of five days. The energy content of the diet was verified by calorimetry and the metabolisable energy derived by the equation